Low-intensity pulsed ultrasound triggers a beneficial neuromodulation in dementia mice with chronic cerebral hypoperfusion via activation of hippocampal Fndc5/irisin signaling.

BACKGROUND: Exercise-related signaling Fndc5/irisin expresses in brain and acts as a crucial regulator of cognitive function, but its detailed roles in vascular dementia (VaD) are still unclear. Low intensity pulsed ultrasound (LIPUS), a novel brain stimulation approach, has been suggested as a promising treatment for dementia. Here, we investigated the activity and efficacy of Fndc5/irisin in experimental VaD, further explored whether the potential effects of LIPUS on VaD is related to Fndc5/irisin. METHODS: Mouse model of VaD was established with chronic cerebral hypoperfusion (CCH) using bilateral common carotid arteries stenosis (BCAS). Transcranial LIPUS was applied 24 h after BCAS and subsequently daily with a stimulation time of 5 min at an ultrasound pressure of 0.51 MPa for a period of 28 days. The levels of Fndc5/irisin in different brain regions, the hippocampal long-term potentiation and anti-inflammatory cytokines were investigated at day 28 after cognitive evaluation. Global Fndc5 knock-out (F5KO), forced expression or knockdown of Fndc5, and recombinant irisin application were respectively employed for mechanism exploration. The neuron dendritic spine density and astrocyte phenotype were detected in vitro. RESULTS: Fndc5/irisin was reduced in hippocampus of BCAS mice, forced expression hippocampal Fndc5 or bilateral intrahippocampal injection of recombinant irisin respectively improved hippocampal synaptic plasticity or inflammatory microenvironment, and then alleviated the cognitive impairments. LIPUS existed a positive efficacy in enhancing hippocampal Fndc5/irisin in BCAS mice, thus triggering a beneficial neuromodulation for VaD protection. Importantly, the neurorestorative effects of LIPUS on CCH-induced damages were totally reversed by knockdown the expression of hippocampal Fndc5 in WT mice, or in F5KO mice. Moreover, Fndc5 mediated the upregulated effects of LIPUS on spine density as well as irisin secretion of hippocampal neurons. The neuron-secreted irisin further drove reactive astrocytes to a neuroprotective phenotype. CONCLUSION: LIPUS induced a neurorestorative stimulation against VaD may be through upregulation of the hippocampal Fndc5/irisin levels. Hippocampal Fndc5/irisin signaling might be a promising strategic target for VaD.

Toward Reagent-Free Discrimination of Alzheimer's Disease Using Blood Plasma Spectral Digital Biomarkers and Machine Learning.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease. The detection of early-stage AD is particularly desirable because it would allow early intervention. However, a minimally invasive, low-cost, and accurate discrimination or diagnostic method for AD is especially difficult in the earliest stage of AD. OBJECTIVE: The aim of this research is to discover blood plasma spectral digital biomarkers of AD, develop a novel intelligent method for the discrimination of AD and accelerate the translation of Fourier transform infrared (FTIR) spectral-based disease discrimination methods from the laboratory to clinical practice. METHODS: Since vibration spectroscopy can provide the structure and chemical composition information of biological samples at the molecular level, we investigated the potential of FTIR spectral biomarkers of blood plasma to differentiate between AD patients and healthy controls. Combined with machine learning technology, we designed a hierarchical discrimination system that provides reagent-free and accurate AD discrimination based on blood plasma spectral digital biomarkers of AD. RESULTS: Accurate segregation between AD patients and healthy controls was achieved with 89.3% sensitivity and 85.7% specificity for early-stage AD patients, 92.8% sensitivity and 87.5% specificity for middle-stage AD patients, and 100% sensitivity and 100% specificity for late-stage AD patients. CONCLUSIONS: Our results show that blood plasma spectral digital biomarkers hold great promise as discrimination markers of AD, indicating the potential for the development of an inexpensive, reagent-free, and less laborious clinical test. As a result, our research outcome will accelerate the clinical application of spectral digital biomarkers and machine learning.

Impact of the COVID-19 Pandemic and Lockdown on Anxiety, Depression and Nursing Burden of Caregivers in Alzheimer's Disease, Dementia With Lewy Bodies and Mild Cognitive Impairment in China: A 1-Year Follow-Up Study.

Background: Many countries have adopted lockdown strategies to prevent the spread of COVID-19. The goal of this study was to investigate the effects of the pandemic on anxiety, depression and care burden in caregivers of nursing patients with Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB) and Mild Cognitive Impairment (MCI), over a one-year period. Methods: We collected data on consecutive patients and their caregivers recruited at T0 (from 30 September to 31 December 2019) before the pandemic of COVID-19 at the memory clinic of Tianjin Huanhu Hospital. The patients and caregivers were followed up on face-to-face at T1 (from 30 September to 31 December 2020) during the pandemic to assess changes in physical activity, social contact, sleep quality, caregiver burden, anxiety and depression. Results: A total of 105 AD, 22 DLB and 50 MCI patients and caregivers were enrolled. A total of 36.6 % of the AD, 81.6% of the DLB, 38% of the MCI caregivers had worsening ZBI, whereas 31.7 % of the AD, 54.4% of the DLB, 26 % of the MCI caregivers had worsening GAD-7, and 29.6 % of the AD, 54.4% of the DLB, and 32 % of the MCI caregivers had worsening PHQ-9. DLB caregivers exhibited a rapid deterioration of ZBI (by 4.27 ± 5.43, P < 0.001), GAD-7 (by 2.23 ± 3.26, P = 0.003) and PHQ-9 (by 1.32 ± 2.25, P = 0.003) compared to AD and MCI caregivers. Conclusion: Social isolation, physical inactivity and sleep disturbance after lockdown for at least 12 months were significantly related to increased caregiver burden and worsened psychological states of caregivers of AD, DLB and MCI sufferers, especially among DLB caregivers.

Pisa syndrome in dementia with Lewy bodies: A Chinese multicenter study.

BACKGROUND: Pisa syndrome (PS) is rarely reported in Dementia with Lewy bodies (DLB). The aim of this article is to investigate the prevalence rate of PS and the correlation with clinical features evaluated in patients with DLB. METHODS: A total of 209 DLB patients were consecutively recruited and underwent standardized clinical evaluation in our multicenter study. The associations between PS and clinical factors were evaluated. RESULTS: The prevalence rate of PS in patients with DLB was 15.3%, which was higher in the moderate and severe stages than mild cognitive impairment and mild stages (81.2% vs. 18.8%). Patients with PS had a longer duration of disease (P = 0.020) and parkinsonism (P = 0.003), higher scores of NPI (P = 0.028), ADL (P = 0.002) and UPDRS part III (P < 0.001), lower scores of clock drawing test (P = 0.009), visuospatial/executive abilities (P = 0.018), attention (P = 0.020), language and praxis (P = 0.020), registration (P = 0.012), greater H&Y stage (P < 0.001), and higher proportion of cholinesterase inhibitors used (P = 0.044) than those without PS. Longer disease duration (OR = 1.166, P = 0.023), presence of parkinsonism (OR = 7.971, P = 0.007), moderate and severe dementia (OR = 3.215, P = 0.021) were associated with the presence of PS. Patients had a longer duration of PS (P = 0.014) and lower mean age of onset (P = 0.040) in the group with severe lateral trunk flexion. CONCLUSION: The development of PS may be associated with longer disease duration, the presence of parkinsonism and severe stages of dementia in DLB. Cholinesterase inhibitors may have a correlation with PS. The severity of lateral flexion is related to the duration of PS and mean age of onset.

Synthesis, Characterization and Cytotoxicity of Alkylated Quercetin Derivatives.

Quercetin, a ubiquitous flavonol, represents a promising leading drug for development of new chemotherapeutic agents. However, its limited cytotoxicity to cancer cells hampers its clinical use. In order to obtain novel quercetin derivatives with superior cytotoxicity, seven alkylated quercetin derivatives were synthesized. Solubility of these derivatives was determined by turbidimetry. Cytotoxicity of the high-soluble derivatives against MCF-7 cells and caco-2 cells was determined using MTT assay. Among these seven products, 7-O-butylquercetin had the highest solubility in DMEM medium and 7-O-geranylquercetin had the most potent cytotoxicity. Further study on cytotoxicity of 7-O-geranylquercetin on NCI-H446, A549, MGC-803 and SGC-7901 cell lines revealed potential antiproliferative effects. The 7-O-geranylquercetin is a broad spectrum cytotoxic agent and it may be a promising leading drug for cancer chemotherapy.

O-Alkylated derivatives of quercetin induce apoptosis of MCF-7 cells via a caspase-independent mitochondrial pathway.

The aim of this study was to investigate the antitumor effects of two novel alkylated derivatives of quercetin, 7-O-butylquercetin (BQ) and 7-O-geranylquercetin (GQ), in MCF-7 human breast cancer cells and explore the possible cellular mechanism of the related apoptotic effects. Our data showed that BQ and GQ were more toxic to MCF-7 cells and had better accumulation ability in MCF-7 cells than quercetin. Morphological observations and DNA fragmentation pattern suggested that the derivatives could induce apoptosis in MCF-7 cells. Derivatives-induced apoptosis could not be reversed by Z-VAD-FMK and N-acetyl cysteine demonstrated that the apoptosis was independent on caspase and reactive oxygen species. Western blot assay showed that endonuclease G and apoptosis inducing factor might be relative to the apoptosis. Alkylation of quercetin at 7-O position can enhance the apoptosis inducing effect and cell accumulation ability relative to quercetin. This structural alteration brings changes on apoptosis pathway as well.